Disposition of suprofen enantiomers in the cat.

Suprofen (SPF) is a non-steroidal anti-inflammatory drug (NSAID), which belongs to the 2-arylpropionic acids subclass. As a result of their chiral characteristics, these compounds have shown a marked enantioselective behaviour with a high degree of interspecies variation. They are mainly eliminated by glucuronidation. Plasma, biliary and urine disposition of SPF was investigated in the cat after intravenous administration of the racemate (dose 2 mg/kg). Both enantiomers exhibited similar disposition profiles in plasma with no evidence of chiral inversion. During bile sampling time, recovered acylglucuronides of R (-) and S (+) SPF were less than 1% of the total dose administered. Only free SPF was recovered in the urine, representing 0.12% of the administered racemic SPF dose. The results indicate that neither chiral inversion nor glucuronidation predominate in SPF disposition in cats.

Covalent binding of suprofen to renal tissue of rat correlates with excretion of its acyl glucuronide.

1. Dosing rat with suprofen produces suprofen equivalents that are covalently bound to plasma and tissue proteins in vivo. 2. Suprofen acyl glucuronide is reactive in vitro, resulting in suprofen equivalents covalently bound to proteins of plasma and tissues in a time-dependent manner. 3. Bile duct ligation of rat increases exposure to suprofen acyl glucuronide in vivo, which leads to enhanced covalent binding of suprofen equivalents to plasma proteins and to kidney tissue. 4. Covalent binding of suprofen equivalents to kidney tissue correlates with excretion of suprofen and suprofen glucuronide by the kidney.

Covalent binding of suprofen acyl glucuronide to albumin in vitro.

1. Suprofen acyl glucuronide, a major metabolite of suprofen in man, is labile, undergoing acyl migration to isomeric conjugates which are not cleaved by beta-glucuronidase. 2. The pH-dependent degradation of diastereomeric suprofen glucuronides in aqueous buffer increases rapidly near physiological pH with an apparent first-order half life of 1.4 h at pH 7.4. 3. Suprofen glucuronide and its isomeric conjugates are reactive with albumin in a pH-dependent manner which corresponds to the stability of the acyl glucuronide. Several per cent of the conjugates added to albumin in solution become covalently bound. 4. The covalent binding of suprofen equivalents to albumin is greatly enhanced by the addition of either cyanide or cyanoborohydride anion, which supports the presence of an imine in the process of binding. Release of isomeric conjugates by treatment of the albumin adduct with dilute acid also supports covalent binding via an imine. 5. The covalent binding of suprofen to proteins through its reactive acyl glucuronide may be of toxicological importance and relevant to the acute renal toxicity observed for suprofen in man.

Suprofen sustained release kinetics in healthy male volunteers. 2nd communication: a multiple dose steady-state kinetics of suprofen sustained release tablets during 6 days in healthy male volunteers.

To 12 healthy male volunteers, who had given their consent, 11 administrations of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) sustained release tablets 600 mg were given twice a day with a dosage interval of 12 h. It could be demonstrated that suprofen given as multiple dose application of sustained release tablets was well tolerated. Effective mean plasma levels were reached after the second dosage. There was no indication of accumulation nor accelerated elimination during the 6-day period. There was no statistically significant difference between the mean plasma curve after the last administration of the 6-day period and the mean plasma curve after the 3rd application. Also the AUC's in the respective intervals turned out not to be statistically significantly different from each other. Clinical and laboratory tests showed no clinically relevant deviations from the normal range. No adverse reactions whatsoever were observed.

Species differences in the metabolism of suprofen in laboratory animals and man.

The metabolism of the oral anti-inflammatory agent suprofen (S), 2-4-(2-thienylcarbonyl)phenyl)propionic acid, has been studied in mice, rats, guinea pigs, dogs, monkeys, and human volunteers. The major metabolites of S in the serum, urine, and feces of these species were determined by GC/MS and HPLC techniques. The metabolic pathways of S in these species involved reduction of the ketone group to an alcohol (S-OH), hydroxylation of the thiophene ring (T-OH), elimination of the thiophene ring to a dicarboxylic acid (S-COOH), and conjugation with glucuronic acid or taurine. In 72-hr urine and feces of these species after po dosing of 1.6 to 2 mg/kg of S, S and these metabolites accounted for 46 to 92% of the dose and were mainly excreted in the urine. S was present as a major product (excreted mainly in conjugated form) in all species. S-OH was a major component in guinea pig and dog but a minor one in other species. T-OH was identified as a major metabolite in monkey, rat, mouse, and man, but a minor one in guinea pig, and it was absent in the dog. S-COOH was present as the minor metabolite in mouse and rat, and present at trace levels in dog, monkey, and man. Conjugation of the propionic acid functionality with taurine was observed only in the dog; in the other species, conjugation with glucuronic acid was extensive. Absorption parameters of S in the rat and monkey were similar to those in man; however, other species were very different from man.

Further structural analysis of urinary metabolites of suprofen in the rat.

The urinary metabolites of 2-(4-(2-thienylcarbonyl)phenyl)propionic acid (suprofen, S) in rats were analyzed by radio-GC, GC/MS, or 1H NMR technique. Radio-GC analysis of trimethylsilylated materials after TLC separation of intact urine showed the presence of three radioactive peaks with the retention times corresponding to the authentic S, 2-(4-(2-thienylhydroxymethyl)phenyl)propionic acid, and 2-(4-carboxyphenyl)propionic acid. About 40% of the total radioactivity appearing in the 0-24-hr urine was accounted for by the three metabolites and their conjugates. The identification of these metabolites was confirmed by comparison of the MS spectra of urine, in which rats were administered an equimolar mixture of S and S[phenyl-d4], with those of synthetic standards. The labile metabolites of S, corresponding to about 32% of the total radioactivity appearing in the 0-24-hr urine, were isolated and purified by ether extraction from the fresh urine and GC/MS or HPLC. GC/MS of the methylated metabolite revealed the consistent presence of the ion peaks at m/z 304, 245, 217, and 141, indicative of a dimethylated product with monohydroxy group on the thiophene ring. Analysis of the 1H NMR spectrum demonstrated the metabolite to be 2-(4-(5-hydroxy-2-thienylcarbonyl)phenyl)propionic acid.

Quantitative determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography.

A sensitive, specific and rapid determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography is described. Plasma or urine samples are directly injected into the liquid chromatograph, which consists of commonly available modules. Manual sample cleanup procedures as well as the addition of an internal standard are not needed. Using 20 microliter-aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 1.0 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 99.2% for plasma and 99.7% for urine samples.